Year: 2010
Type: article
Abstract: Histoplasma capsulatum is a dimorphic fungus that can cause lethal infection in immunocompromised hosts.In order to resolve infection, the host must mount a T H 1 immune response that is accompanied by an influx of inflammatory cells to the primary site of infection, the lung.Chemokines regulate cell recruitment and T H 1/T H 2 polarization; however, the role of chemokines in control of H. capsulatum infection has not been explored.We have demonstrated that the chemokine receptor CCR2 is requisite for protective immunity to H. capsulatum.H. capsulatum infected CCR2 -/-mice manifested defects in inflammatory cell recruitment, increased interleukin (IL)-4, and progressive infection.Increased IL-4 in CCR2 -/-mice diminished host resistance as demonstrated by the ability of IL-4-neutralized CCR2 -/-mice to resolve infection without altering cell recruitment.In contrast, mice lacking CCL2, a major CCR2 ligand, did not exhibit elevated IL-4 and resolved infection.Lack of both CCL2 and the CCR2 ligand CCL7 produced a phenotype similar to that observed in CCR2 -/-mice demonstrating for the first time that CCL2 and CCL7 mutually regulate IL-4.We examined the cellular sources that contributed to IL-4 production in lungs of CCR2 -/-mice.Surprisingly, numerous alveolar macrophages and dendritic cells (DC) secreted IL-4 in addition to CD4 + T cells at the peak of infection.We explored the mechanism by which IL-4 exacerbated infection.Elevations of IL-4 in CCR2 -/- mice were associated with alternatively activated MI which exhibited increased arginase-1.Administration of L-arginine, an arginase-1 substrate, or BEC ((S)-(2-Boronoethyl)-L-cysteine, HCl), an arginase-1 inhibitor, partially decreased fungal burden in CCR2 -/-mice indicating that increased arginase-1 expression is deleterious to host defense.We investigated the mechanism by which IL-4 becomes elevated in lungs of CCR2 -/-mice.Infected CCR2 -/-or CCL2-CCL7 deficient mice exhibited a marked decrement in the number of CD8 -conventional DC in lungs, therefore we hypothesized that these cells restrict IL-4 generation.Adoptive transfer of antigen (Ag)-loaded WT bone marrow-derived DC (Ag-BMDC) to WT or CCR2 -/-mice resulted in suppression of IL-4 whereas adoptive transfer of BMDC that were not exposed to Ag had no effect.Transfer of Ag-BMDC lacking CCR2 also limited IL-4 generation.We asked if DCmediated MHCII-Ag presentation to CD4 + T cells was necessary for IL-4 restriction.MHCII -/- Ag-BMDC did not limit IL-4 when transferred to CCR2 -/-mice and depletion of CD4 + T cells prior to, but not at the initiation of infection, resulted in decreased IL-4 indicating that Ag-BMDC suppression of IL-4 is dependent on limiting production by CD4 + T cells early during infection.Fungal burden was not reduced in CD4-depleted CCR2 -/-mice but CCR2 -/-mice that received Ag-BMDC in addition to depletion of CD4 + T cells were able to control infection.Together, the data suggest that elevated IL-4 in CCR2 -/-mice arises from decreased recruitment of DC capable of presenting antigen.Furthermore, CD4 + T cells dampen immunity in H. capsulatum infected-CCR2 -/-mice. Chapter 2: The CCL7-CCL2-CCR2 Axis Regulates IL-4 Production in Lungs and Fungal Immunity 2
Author: Wendy Szymczak
Institution: University of Cincinnati
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2243406514