Helminth infections provoke a T helper type 2 (Th2) cell response, which is critical for protective immunity. Although it is clear that Th2 cells play an essential role in limiting parasite burden, these same responses also cause chronic helminth-induced inflammation. Moreover, Th2 cytokine responses are also involved in the detrimental inflammation associated with allergy, asthma and chronic obstructive pulmonary disease (COPD). Therefore, a better understanding of how Th2 cell responses are regulated could offer new opportunities to design treatments both to promote anti-parasite immunity and limit Th2 cytokine-associated inflammatory disorders. The secreted protein RELMa was recently identified as a potent immuno-regulatory molecule that could limit inflammation in multiple helminth infection models. In this proposal, we will employ a model of hookworm infection-induced lung inflammation to delineate how RELMa expression is regulated, and to determine the downstream targets of RELMa-mediated inhibition of lung inflammation. Our preliminary data demonstrate that infection with Nippostrongylus brasiliensis (Nb) promotes chronic lung inflammation that is associated with RELMa expression by epithelial cells, alternatively activated macrophages and eosinophils. Further, RELMa-deficient (Retnla-/-) mice exhibited exacerbated chronic lung inflammation, and increased macrophage and Th2 cytokine responses. However, the factors that promote RELMa expression and the cell lineage-restricted requirements for RELMa-mediated tissue protection are unknown. Additionally, the downstream factors and cell-types mediating exacerbated lung inflammation in Retnla-/- mice are undefined.
In Aim 1, the combined approaches of cell-specific deletions, bone marrow chimeras and cell transfers will be employed to identify the cell types and cell-derived factors that promote RELMa expression, and the mechanism through which RELMa limits Nb-induced chronic lung inflammation. Knowledge of what regulates RELMa expression, and how RELMa mediates tissue protection, could provide new opportunities to harness the biologic function of RELMa for therapies to treat or prevent lung inflammation. In our preliminary data investigating how Nb-induced RELMa expression in the lung is initiated, a previously unrecognized pathway of macrophage-basophil cross-regulation was uncovered, in which basophils induce macrophage recruitment and expression of RELMa. Further, RELMa provides a negative feedback regulation to limit basophil function. Based on these findings, Aim 2 will employ both Nb infection and an in vivo model of lung basophilia to examine how basophils mediate macrophage activation and expression of RELMa. Finally, a novel macrophage-basophil co-culture system will be employed to delineate the molecular mechanisms of basophil-macrophage cross-regulation. Given the emergence of basophils as critical innate cells in Th2 cytokine responses, investigating how basophil:macrophage interactions are regulated could increase our understanding of how to manipulate Th2 cytokine-dependent immunity and inflammation.

Public Health Relevance

Soil transmitted helminth parasites infect an estimated two billion people and represent a significant global public health problem. While certain aspects of the anti-parasite immune response are critical for reducing parasite burden, they are also known to contribute to chronic helminth-induced disease as well as to the detrimental inflammation associated with allergy, asthma and chronic obstructive pulmonary disease. In this proposal, we will delineate the role of the secreted protein RELMa in limiting excessive helminth-induced lung inflammation, and predict that our findings will increase our understanding of how to treat chronic lung inflammation associated with infection, asthma or allergy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI091759-04S1
Application #
8914741
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Davidson, Wendy F
Project Start
2011-03-01
Project End
2016-02-29
Budget Start
2014-08-21
Budget End
2015-02-28
Support Year
4
Fiscal Year
2014
Total Cost
$54,182
Indirect Cost
$18,536
Name
University of California Riverside
Department
None
Type
Schools of Medicine
DUNS #
627797426
City
Riverside
State
CA
Country
United States
Zip Code
92521
Chen, Gang; Wang, Spencer H; Jang, Jessica C et al. (2016) 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 84:1100-11
Bennett, Kaila M; Parnell, Erinn A; Sanscartier, Candice et al. (2016) Induction of Colonic M Cells during Intestinal Inflammation. Am J Pathol 186:1166-79
Chellappa, Karthikeyani; Deol, Poonamjot; Evans, Jane R et al. (2016) Opposing roles of nuclear receptor HNF4α isoforms in colitis and colitis-associated colon cancer. Elife 5:
Nair, Meera G; Herbert, De'Broski R (2016) Immune polarization by hookworms: taking cues from T helper type 2, type 2 innate lymphoid cells and alternatively activated macrophages. Immunology 148:115-24
Jang, Jessica C; Chen, Gang; Wang, Spencer H et al. (2015) Macrophage-derived human resistin is induced in multiple helminth infections and promotes inflammatory monocytes and increased parasite burden. PLoS Pathog 11:e1004579
Barnes, Mark A; Carson, Monica J; Nair, Meera G (2015) Non-traditional cytokines: How catecholamines and adipokines influence macrophages in immunity, metabolism and the central nervous system. Cytokine 72:210-9
Bergstrom, Kirk S B; Morampudi, Vijay; Chan, Justin M et al. (2015) Goblet Cell Derived RELM-β Recruits CD4+ T Cells during Infectious Colitis to Promote Protective Intestinal Epithelial Cell Proliferation. PLoS Pathog 11:e1005108
Chen, Gang; Chan, Alexander J; Chung, Josiah I et al. (2014) Polarizing the T helper 17 response in Citrobacter rodentium infection via expression of resistin-like molecule α. Gut Microbes 5:363-8
Jang, Jessica C; Nair, Meera G (2013) Alternatively Activated Macrophages Revisited: New Insights into the Regulation of Immunity, Inflammation and Metabolic Function following Parasite Infection. Curr Immunol Rev 9:147-156
Gad, Wael; Nair, Meera G; Van Belle, Karolien et al. (2013) The quiescin sulfhydryl oxidase (hQSOX1b) tunes the expression of resistin-like molecule alpha (RELM-α or mFIZZ1) in a wheat germ cell-free extract. PLoS One 8:e55621

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