Faculty Collaboration Database

Role of neutrophils in IL-17-dependent immunity to mucosal candidiasis. J Immunol 2014 Feb 15;192(4):1745-52

Date

01/21/2014

Pubmed ID

24442441

Pubmed Central ID

PMC3946223

DOI

10.4049/jimmunol.1302265

Scopus ID

2-s2.0-84894270649 (requires institutional sign-in at Scopus site)   120 Citations

Abstract

Oropharyngeal candidiasis (OPC), caused by the commensal fungus Candida albicans, is an opportunistic infection associated with infancy, AIDS, and IL-17-related primary immunodeficiencies. The Th17-associated cytokines IL-23 and IL-17 are crucial for immunity to OPC, but the mechanisms by which they mediate immunity are poorly defined. IL-17RA-deficient humans and mice are strongly susceptible to OPC, with reduced levels of CXC chemokines and concomitantly impaired neutrophil recruitment to the oral mucosa. Paradoxically, humans with isolated neutropenia are typically not susceptible to candidiasis. To determine whether immunity to OPC is mediated via neutrophil recruitment, mice lacking CXCR2 were subjected to OPC and were found to be highly susceptible, although there was no dissemination of fungi to peripheral organs. To assess whether the entire neutrophil response is IL-17 dependent, IL-17RA(-/-) and IL-23(-/-) mice were administered neutrophil-depleting Abs and subjected to OPC. These mice displayed increased oral fungal burdens compared with IL-17RA(-/-) or IL-23(-/-) mice alone, indicating that additional IL-17-independent signals contribute to the neutrophil response. WT mice treated with anti-Gr-1 Abs exhibited a robust infiltrate of CD11b(+)Ly-6G(low)F4/80(-) cells to the oral mucosa but were nonetheless highly susceptible to OPC, indicating that this monocytic influx is insufficient for host defense. Surprisingly, Ly-6G Ab treatment did not induce the same strong susceptibility to OPC in WT mice. Thus, CXCR2(+) and Gr-1(+) neutrophils play a vital role in host defense against OPC. Moreover, defects in the IL-23/17 axis cause a potent but incomplete deficiency in the neutrophil response to oral candidiasis.

Author List

Huppler AR, Conti HR, Hernández-Santos N, Darville T, Biswas PS, Gaffen SL

Author

Anna Huppler MD Associate Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antigens, Differentiation
Antigens, Ly
CD11b Antigen
Candida albicans
Candidiasis, Oral
Interleukin-17
Interleukin-23 Subunit p19
Mice
Mice, Inbred C57BL
Mice, Knockout
Mouth Mucosa
Neutrophil Infiltration
Neutrophils
Receptors, Chemokine
Receptors, Interleukin-17
Receptors, Interleukin-8B
Th17 Cells