| First Author | Li J | Year | 2021 |
| Journal | Front Immunol | Volume | 12 |
| Pages | 710406 | PubMed ID | 34349768 |
| Mgi Jnum | J:350365 | Mgi Id | MGI:6817203 |
| Doi | 10.3389/fimmu.2021.710406 | Citation | Li J, et al. (2021) Macrophage-Regulatory T Cell Interactions Promote Type 2 Immune Homeostasis Through Resistin-Like Molecule alpha. Front Immunol 12:710406 |
| abstractText | RELMalpha 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, RELMalpha is highly expressed by peritoneal macrophages, however, its function in the serosal cavity is unclear. In this study, we generated RELMalpha TdTomato (Td) reporter/knockout (Ralpha(Td)) mice and investigated RELMalpha function in IL-4 complex (IL-4c)-induced peritoneal inflammation. We first validated the RELMalpha(Td/Td) transgenic mice and showed that IL-4c injection led to the significant expansion of large peritoneal macrophages that expressed Td but not RELMalpha protein, while RELMalpha(+/+) mice expressed RELMalpha and not Td. Functionally, RELMalpha(Td/Td) mice had increased IL-4 induced peritoneal macrophage responses and splenomegaly compared to RELMalpha(+/+) mice. Gene expression analysis indicated that RELMalpha(Td/Td) peritoneal macrophages were more proliferative and activated than RELMalpha(+/+) 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 Ralpha(Td/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 RELMalpha(+/+) or RELMalpha(Td/Td) macrophages, however, RELMalpha(Td/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 RELMalpha(Td/Td) spleens compared to RELMalpha(+/+) spleens. Taken together, these studies identify a new RELMalpha regulatory pathway whereby RELMalpha-expressing macrophages directly sustain Treg proliferation to limit type 2 inflammatory responses. |
