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 #
5R01AI091759-02
Application #
8435260
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Davidson, Wendy F
Project Start
2011-03-01
Project End
2013-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$400,000
Indirect Cost
$150,000
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Pine, Gabrielle M; Batugedara, Hashini M; Nair, Meera G (2018) Here, there and everywhere: Resistin-like molecules in infection, inflammation, and metabolic disorders. Cytokine 110:442-451
Batugedara, Hashini M; Argueta, Donovan; Jang, Jessica C et al. (2018) Host- and Helminth-Derived Endocannabinoids That Have Effects on Host Immunity Are Generated during Infection. Infect Immun 86:
Jang, Jessica C; Li, Jiang; Gambini, Luca et al. (2017) Human resistin protects against endotoxic shock by blocking LPS-TLR4 interaction. Proc Natl Acad Sci U S A 114:E10399-E10408
Landrith, Tyler A; Sureshchandra, Suhas; Rivera, Andrea et al. (2017) CD103+ CD8 T Cells in the Toxoplasma-Infected Brain Exhibit a Tissue-Resident Memory Transcriptional Profile. Front Immunol 8:335
Chen, Gang; Wang, Spencer H; Jang, Jessica C et al. (2016) Comparison of RELM? and RELM? Single- and Double-Gene-Deficient Mice Reveals that RELM? Expression Dictates Inflammation and Worm Expulsion in Hookworm Infection. Infect Immun 84:1100-1111
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
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
Chellappa, Karthikeyani; Deol, Poonamjot; Evans, Jane R et al. (2016) Opposing roles of nuclear receptor HNF4? isoforms in colitis and colitis-associated colon cancer. Elife 5:
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-? Recruits CD4+ T Cells during Infectious Colitis to Promote Protective Intestinal Epithelial Cell Proliferation. PLoS Pathog 11:e1005108

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