[en] Resistin-like molecule alpha (RELMalpha) is a highly secreted protein in type 2 (Th2) cytokine-induced inflammation including helminth infection and allergy. In infection with Nippostrongylus brasiliensis (Nb), RELMalpha dampens Th2 inflammatory responses. RELMalpha is expressed by immune cells, and by epithelial cells (EC); however, the functional impact of immune versus EC-derived RELMalpha is unknown. We generated bone marrow (BM) chimeras that were RELMalpha deficient (RELMalpha(-/) (-) ) in BM or non BM cells and infected them with Nb. Non BM RELMalpha(-/-) chimeras had comparable inflammatory responses and parasite burdens to RELMalpha(+/+) mice. In contrast, both RELMalpha(-/-) and BM RELMalpha(-/-) mice exhibited increased Nb-induced lung and intestinal inflammation, correlated with elevated Th2 cytokines and Nb killing. CD11c(+) lung macrophages were the dominant BM-derived source of RELMalpha and can mediate Nb killing. Therefore, we employed a macrophage-worm co-culture system to investigate whether RELMalpha regulates macrophage-mediated Nb killing. Compared to RELMalpha(+) (/+) macrophages, RELMalpha(-/-) macrophages exhibited increased binding to Nb and functionally impaired Nb development. Supplementation with recombinant RELMalpha partially reversed this phenotype. Gene expression analysis revealed that RELMalpha decreased cell adhesion and Fc receptor signaling pathways, which are associated with macrophage-mediated helminth killing. Collectively, these studies demonstrate that BM-derived RELMalpha is necessary and sufficient to dampen Nb immune responses, and identify that one mechanism of action of RELMalpha is through inhibiting macrophage recruitment and interaction with Nb. Our findings suggest that RELMalpha acts as an immune brake that provides mutually beneficial effects for the host and parasite by limiting tissue damage and delaying parasite expulsion.
Urban JF, Katona IM, Paul WE, Finkelman FD. Interleukin 4 is important in protective immunity to a gastrointestinal nematode infection in mice. Proc Natl Acad Sci U S A. 1991;88:5513–5517
Finkelman FD, Shea-Donohue T, Morris SC, et al. Interleukin-4- and interleukin-13-mediated host protection against intestinal nematode parasites. Immunol Rev. 2004;201:139–155
Grencis RK. Immunity to helminths: resistance, regulation, and susceptibility to gastrointestinal nematodes. Annu Rev Immunol. 2015;33:201–225
Nono JK, Ndlovu H, Abdel Aziz N, Mpotj T, Hlak L, Brombache F. Interleukin-4 receptor alpha is still required after Th2 polarization for the maintenance and the recall of protective immunity to nematode infection. PLoS Negl Trop Dis. 2017;11:e0005675
Chen F, Liu Z, Wu W, et al. An essential role for TH2-type responses in limiting acute tissue damage during experimental helminth infection. Nat Med. 2012;18:260–266
Gause WC, Wynn TA, Allen JE. Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths. Nat Rev Immunol. 2013;13:607–614
Novak ML, Koh TJ. Macrophage phenotypes during tissue repair. J Leukoc Biol. 2013;93:875–881
Chiaramonte MG, Cheever AW, Malley JD, Donaldson DD, Wynn TA. Studies of murine schistosomiasis reveal interleukin-13 blockade as a treatment for established and progressive liver fibrosis. Hepatology. 2001;34:273–282
Fallon PG, Emson CL, Smith P, McKenzie AN. IL-13 overexpression predisposes to anaphylaxis following antigen sensitization. J Immunol. 2001;166:2712–2716
Gause WC, David A, eds. The Th2 Type Immune Response in Health and Disease: From Host Defense and Allergy to Metabolic Homeostasis and Beyond. Springer; 2015
Holcomb IN, Kabakoff RC, Chan B, et al. FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J. 2000;19:4046–4055
Steppan CM, Brown EJ, Wright CM, et al. A family of tissue-specific resistin-like molecules. Proc Natl Acad Sci U S A. 2001;98:502–506
Nair MG, Du Y, Perrigoue JG, et al. Alternatively activated macrophage-derived RELM- is a negative regulator of type 2 inflammation in the lung. J Exp Med. 2009;206:937–952
Munitz A, Waddell A, Seidu L, et al. Resistin-like molecule alpha enhances myeloid cell activation and promotes colitis. J Allergy Clin Immunol. 2008;122:1200–1207
Munitz A, Seidu L, Cole ET, Ahrens R, Hogan SP, Rothenberg ME. Resistin-like molecule alpha decreases glucose tolerance during intestinal inflammation. J Immunol. 2009;182:2357–2363
Bokarewa M, Nagaev I, Dahlberg L, Smith U, Tarkowski A. Resistin, an adipokine with potent proinflammatory properties. J Immunol. 2005;174:5789–5795
Munitz A, Cole ET, Karo-Atar D, Finkelman FD, Rothenberg ME. Resistin-like molecule-α regulates IL-13-induced chemokine production but not allergen-induced airway responses. Am J Respir Cell Mol Biol. 2012;46:703–713
Dong L, Wang SJ, Camoretti-Mercado B, Li HJ, Chen M, Bi WX. FIZZ1 plays a crucial role in early stage airway remodeling of OVA-induced asthma. J Asthma. 2008;45:648–653
Chen G, Wang SH, Jang JC, Odegaard JI, Nair MG. Comparison of RELMα and RELMβ single- and double-gene-deficient mice reveals that RELMα expression dictates inflammation and worm expulsion in hookworm infection. Infect Immun. 2016;84:1100–1111
Lee MR, Shim D, Yoon J, et al. Retnla overexpression attenuates allergic inflammation of the airway. PLoS One. 2014;9:e112666
Pesce JT, Ramalingam TR, Wilson MS, et al. Retnla (relmalpha/fizz1) suppresses helminth-induced Th2-type immunity. PLoS Pathog. 2009;5:e1000393
Siracusa MC, Reece JJ, Urban JF, Scott AL. Dynamics of lung macrophage activation in response to helminth infection. J Leukoc Biol. 2008;84:1422–1433
Cook PC, Jones LH, Jenkins SJ, Wynn TA, Allen JE, MacDonald AS. Alternatively activated dendritic cells regulate CD4+ T-cell polarization in vitro and in vivo. Proc Natl Acad Sci U S A. 2012;109:9977–9982
Raes G, De Baetselier P, Noël W, Beschin A, Brombacher F, Hassanzade Gh G. Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated macrophages. J Leukoc Biol. 2002;71:597–602
Wills-Karp M, Rani R, Dienger K, et al. Trefoil factor 2 rapidly induces interleukin 33 to promote type 2 immunity during allergic asthma and hookworm infection. J Exp Med. 2012;209:607–622
Esser-von Bieren J, Mosconi I, Guiet R, et al. Antibodies trap tissue migrating helminth larvae and prevent tissue damage by driving IL-4Rα-independent alternative differentiation of macrophages. PLoS Pathog. 2013;9:e1003771
Tomfohr J, Lu J, Kepler TB. Pathway level analysis of gene expression using singular value decomposition
Nair MG, Gallagher IJ, Taylor MD, et al. Chitinase and Fizz family members are a generalized feature of nematode infection with selective upregulation of Ym1 and Fizz1 by antigen-presenting cells. Infect Immun. 2005;73:385–394
Chen F, Wu W, Millman A, et al. Neutrophils prime a long-lived effector macrophage phenotype that mediates accelerated helminth expulsion. Nat Immunol. 2014;15:938–946
Su Q, Zhou Y, Johns RA. Bruton's tyrosine kinase (BTK) is a binding partner for hypoxia induced mitogenic factor (HIMF/FIZZ1) and mediates myeloid cell chemotaxis. FASEB J. 2007;21:1376–1382
Li D, Fernandez LG, Dodd-o J, Langer J, Wang D, Laubach VE. Upregulation of hypoxia-induced mitogenic factor in compensatory lung growth after pneumonectomy. Am J Respir Cell Mol Biol. 2005;32:185–191
Teng X, Li D, Champion HC, Johns RA. FIZZ1/RELMα, a novel hypoxia-induced mitogenic factor in lung with vasoconstrictive and angiogenic properties. Circulation Research. 2003;92:1065–1067
Gao JL, Chen H, Filie JD, Kozak CA, Murphy PM. Differential expansion of the N-formylpeptide receptor gene cluster in human and mouse. Genomics. 1998;51:270–276
Turnbull IR, Gilfillan S, Cella M, et al. Cutting edge: tREM-2 attenuates macrophage activation. J Immunol. 2006;177:3520–3524
Harvie M, Camberis M, Tang SC, Delahunt B, Paul W, Le Gros G. The lung is an important site for priming CD4 T-cell-mediated protective immunity against gastrointestinal helminth parasites. Infect Immun. 2010;78:3753–3762
Thawer SG, Horsnell WG, Darby M, et al. Lung-resident CD4⁺ T cells are sufficient for IL-4Rα-dependent recall immunity to Nippostrongylus brasiliensis infection. Mucosal Immunol. 2014;7:239–248
Horsnell WG, Darby MG, Hoving JC, et al. IL-4Rα-associated antigen processing by B cells promotes immunity in Nippostrongylus brasiliensis infection. PLoS Pathog. 2013;9:e1003662
Nair MG, Herbert DR. Immune polarization by hookworms: taking cues from T helper type 2, type 2 innate lymphoid cells and alternatively activated macrophages. Immunology. 2016;148:115–124
Borthwick LA, Barron L, Hart KM, et al. Macrophages are critical to the maintenance of IL-13-dependent lung inflammation and fibrosis. Mucosal Immunol. 2016;9:38–55
Zhao A, Urban JF, Anthony RM, et al. Th2 cytokine-induced alterations in intestinal smooth muscle function depend on alternatively activated macrophages. Gastroenterology. 2008;135:217–225
Loke P, Nair MG, Parkinson J, Guiliano D, Blaxter M, Allen JE. IL-4 dependent alternatively-activated macrophages have a distinctive in vivo gene expression phenotype. BMC Immunol. 2002;3:7
Artis D, Wang ML, Keilbaugh SA, et al. RELMbeta/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. Proc Natl Acad Sci U S A. 2004;101:13596–13600
Herbert DR, Yang JQ, Hogan SP, et al. Intestinal epithelial cell secretion of RELM-beta protects against gastrointestinal worm infection. J Exp Med. 2009;206:2947–2957
Le Y, Murphy PM, Wang JM. Formyl-peptide receptors revisited. Trends Immunol. 2002;23:541–548
Endo Y, Iwaki D, Ishida Y, Takahashi M, Matsushita M, Fujita T. Mouse ficolin B has an ability to form complexes with mannose-binding lectin-associated serine proteases and activate complement through the lectin pathway. J Biomed Biotechnol. 2012;105891
Bonne-Année S, Kerepesi LA, Hess JA, et al. Human and mouse macrophages collaborate with neutrophils to kill larval Strongyloides stercoralis. Infect Immun. 2013;81:3346–3355
Guo YL, Bai R, Chen CX, et al. Role of junctional adhesion molecule-like protein in mediating monocyte transendothelial migration. Arterioscler Thromb Vasc Biol. 2009;29:75–83
Wei W, Mok SC, Oliva E, Kim SH, Mohapatra G, Birrer MJ. FGF18 as a prognostic and therapeutic biomarker in ovarian cancer. J Clin Invest. 2013;123:4435–4448
Knipper JA, Willenborg S, Brinckmann J, et al. Interleukin-4 receptor α signaling in myeloid cells controls collagen fibril assembly in skin repair. Immunity. 2015;43:803–816
Caley MP, Martins VL, O'Toole EA. Metalloproteinases and Wound Healing. Adv Wound Care (New Rochelle). 2015;4:225–234
Liu T, Yu H, Ullenbruch M, et al. The in vivo fibrotic role of FIZZ1 in pulmonary fibrosis. PLoS One. 2014;9:e88362
Horikawa S, Ishii Y, Hamashima T, et al. PDGFRα plays a crucial role in connective tissue remodeling. Sci Rep. 2015;5:17948
Isaac R, Goldstein I, Furth N, et al. TM7SF3, a novel p53-regulated homeostatic factor, attenuates cellular stress and the subsequent induction of the unfolded protein response. Cell Death Differ. 2017;24:132–143
Rouault JP, Falette N, Guéhenneux F, et al. Identification of BTG2, an antiproliferative p53-dependent component of the DNA damage cellular response pathway. Nat Genet. 1996;14:482–486
Yamaji-Kegan K, Takimoto E, Zhang A, et al. Hypoxia-induced mitogenic factor (FIZZ1/RELMα) induces endothelial cell apoptosis and subsequent interleukin-4-dependent pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2014;306:L1090–L1103
Tong Q, Zheng L, Li B, et al. Hypoxia-induced mitogenic factor enhances angiogenesis by promoting proliferation and migration of endothelial cells. Exp Cell Res. 2006;312:3559–3569
Patel J, McNeill E, Douglas G, et al. RGS1 regulates myeloid cell accumulation in atherosclerosis and aortic aneurysm rupture through altered chemokine signalling. Nat Commun. 2015;6:6614
Lamb EW, Crow ET, Lim KC, Liang YS, Lewis FA, Davies SJ. Conservation of CD4+ T cell-dependent developmental mechanisms in the blood fluke pathogens of humans. Int J Parasitol. 2007;37:405–415
Riner DK, Ferragine CE, Maynard SK, Davies SJ. Regulation of innate responses during pre-patent schistosome infection provides an immune environment permissive for parasite development. PLoS Pathog. 2013;9:e1003708
Lamb EW, Walls CD, Pesce JT, et al. Blood fluke exploitation of non-cognate CD4+ T cell help to facilitate parasite development. PLoS Pathog. 2010;6:e1000892
Bouchery T, Filbey K, Shepherd A, et al. A novel blood-feeding detoxification pathway in Nippostrongylus brasiliensis L3 reveals a potential checkpoint for arresting hookworm development. PLoS Pathog. 2018;14:e1006931
Harris NL, Loke P. Recent advances in type-2-cell-mediated immunity: Insights from Helminth infection. Immunity. 2017;47:1024–1036
Moog-Lutz C, Cavé-Riant F, Guibal FC, et al. JAML, a novel protein with characteristics of a junctional adhesion molecule, is induced during differentiation of myeloid leukemia cells. Blood. 2003;102:3371–3378
Luster AD, Alon R, von Andrian UH. Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol. 2005;6:1182–1190
Mackay CR. Moving targets: cell migration inhibitors as new anti-inflammatory therapies. Nat Immunol. 2008;9:988–998
Reim I, Hollfelder D, Ismat A, Frasch M. The FGF8-related signals Pyramus and Thisbe promote pathfinding, substrate adhesion, and survival of migrating longitudinal gut muscle founder cells. Dev Biol. 2012;368:28–43
VanCompernolle SE, Clark KL, Rummel KA, Todd SC. Expression and function of formyl peptide receptors on human fibroblast cells. J Immunol. 2003;171:2050–2056
Sadanandam A, Rosenbaugh EG, Singh S, Varney M, Singh RK. Semaphorin 5A promotes angiogenesis by increasing endothelial cell proliferation, migration, and decreasing apoptosis. Microvasc Res. 2010;79:1–9
Endo Y, Takahashi M, Iwaki D, et al. Mice deficient in ficolin, a lectin complement pathway recognition molecule, are susceptible to Streptococcus pneumoniae infection. J Immunol. 2012;189:5860–5866
Sibilano R, Gaudenzio N, DeGorter MK, et al. A TNFRSF14-FcɛRI-mast cell pathway contributes to development of multiple features of asthma pathology in mice. Nat Commun. 2016;7:13696
Lu P, Takai K, Weaver VM, Werb Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb Perspect Biol. 2011:3
Szerlip NJ, Pedraza A, Chakravarty D, et al. Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc Natl Acad Sci U S A. 2012;109:3041–3046
Kornfeld JW, Baitzel C, Könner AC, et al. Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b. Nature. 2013;494:111–115
Attery A, Batra JK. Mouse eosinophil associated ribonucleases: Mechanism of cytotoxic, antibacterial and antiparasitic activities. Int J Biol Macromol. 2017;94:445–450
