Abstract
RELMα is a small, secreted protein expressed by type 2 cytokine-activated “M2” macrophages in helminth infection and allergy. At steady state and in response to type 2 cytokines, RELMα is highly expressed by peritoneal macrophages, however, its function in the serosal cavity is unclear. In this study, we generated RELMα TdTomato (Td) reporter/knockout (RαTd) mice and investigated RELMα function in IL-4 complex (IL-4c)-induced peritoneal inflammation. We first validated the RELMαTd/Td transgenic mice and showed that IL-4c injection led to the significant expansion of large peritoneal macrophages that expressed Td but not RELMα protein, while RELMα+/+ mice expressed RELMα and not Td. Functionally, RELMαTd/Td mice had increased IL-4 induced peritoneal macrophage responses and splenomegaly compared to RELMα+/+ mice. Gene expression analysis indicated that RELMαTd/Td peritoneal macrophages were more proliferative and activated than RELMα+/+ macrophages, with increased genes associated with T cell responses, growth factor and cytokine signaling, but decreased genes associated with differentiation and maintenance of myeloid cells. We tested the hypothesis that RαTd/Td macrophages drive aberrant T cell activation using peritoneal macrophage and T cell co-culture. There were no differences in CD4+ T cell effector responses when co-cultured with RELMα+/+ or RELMαTd/Td macrophages, however, RELMαTd/Td macrophages were impaired in their ability to sustain proliferation of FoxP3+ regulatory T cells (Treg). Supportive of the in vitro results, immunofluorescent staining of the spleens revealed significantly decreased FoxP3+ cells in the RELMαTd/Td spleens compared to RELMα+/+ spleens. Taken together, these studies identify a new RELMα regulatory pathway whereby RELMα-expressing macrophages directly sustain Treg proliferation to limit type 2 inflammatory responses.
Highlights
Macrophages are a dominant resident population within the peritoneal cavity with critical immune surveillance and homeostatic functions [1]
Resistin-like molecule a (RELMa) in homeostatic conditions, RELMa expression is dramatically elevated in a type 2 cytokine environment such as helminth infection or IL-4 complex (IL-4c) injection [17]
Peritoneal macrophages follow similar activation pathways to other macrophage lineages, where M1 macrophages activated by IFNg and TNFa have enhanced microbicidal or tumoricidal capacity and secrete high levels of pro-inflammatory cytokines and mediators [60], while IL-4 activated M2 macrophages reduce inflammation and contribute to tissue repair through secretion of IL-10 and TGF-b [61, 62]
Summary
Macrophages are a dominant resident population within the peritoneal cavity with critical immune surveillance and homeostatic functions [1]. As sentinels, they are rapid responders to microbial invasion resulting from injury of the serous organs, such as the spleen, liver and intestinal tract, and can be mobilized to traffic to the injured organ and mediate tissue repair [2]. Identification of peritoneal macrophagederived factors and activation markers that cause beneficial or pathologic outcomes would provide insight into their biology and identify targets for treatment of serous cavity-associated disease. In type 2 cytokinepolarized environments such as helminth infection or in vivo IL4 complex injection, RELMa expression is dramatically elevated reaching 100% expression by small and large peritoneal macrophages [14]. RELMa, known as FIZZ1 and HIMF, was originally identified as a highly secreted protein in the lung during allergic airway inflammation [15], it is well-recognized that RELMa is pleiotropically expressed throughout the body, and a signature gene expressed by M2-
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
