Early Immunological Response to German Cockroach Frass Exposure Induces a Th2/Th17 Environment

Abstract

Cockroach exposure is a major risk factor for the development of asthma; however, the early immune events induced by cockroach leading to the Th2 response are not fully understood. Exposure of naïve mice to German cockroach (GC) feces (frass) was sufficient to induce dendritic cell (DC) recruiting and activating chemokines C-C motif ligand 20, granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor and macrophage inflammatory protein-1α into the airways. This corresponded with an increase in myeloid DCs (mDCs) in the airways as well as increased expression of CD80 and CD86 on the mDCs. Plasmacytoid DCs in the lung were unchanged. Levels of IL-5, IL-17A and IL-6 cytokines in whole lung cultures were significantly increased 18 h following GC frass exposure demonstrating the early development of a mixed Th2/Th17 response. In addition, GC frass stimulated the production of IL-23, IL-6 and IL-12p70 from bone marrow-derived mDCs. Adoptive transfer of GC frass-pulsed mDCs induced airway reactivity, airway inflammation as well as eosinophilia and induced a strong Th2/Th17 response in the lung. MyD88-deficient bone marrow-derived mDCs did not respond to GC frass treatment, suggesting a functional Toll-like receptor pathway was important to induce the Th2/Th17 response. Together, our data show that GC frass activated the innate immune response to augment DC recruitment and activation of mDCs which promoted robust T cell-skewing cytokines and ultimately drive the development of airway inflammation.

Emergence, origin, and function of neutrophil–dendritic cell hybrids in experimentally induced inflammatory lesions in mice

“…We examined the emergence of neutrophil-DC hybrids in the following inflammation models: acute peritonitis induced by intraperitoneal injection of 3% thioglycollate or live E. coli, chronic skin inflammation in KC-Tie2 TG mice, 16 acute lung inflammation induced by intratracheal administration of German cockroach (GC) frass extracts, 18,19 and acute bacterial lymphadenitis induced by subcutaneous injection of E. coli. Single cell suspensions were prepared as described previously.…”

“…Single cell suspensions were prepared as described previously. [18][19][20] Methods for these inflammation models are described in detail in the supplemental data ("Methods"). 12,13 We interpreted this negative result to imply that generation of neutrophil-DC hybrids might require inflammatory signals leading to neutrophil recruitment and GM-CSF production.…”

“…Rapid and profound recruitment of neutrophils occurs in lung after intratracheal administration of GC frass extracts as reported previously. 18,19 Significant, albeit modest, numbers of hybrids (corresponding to ;2% of traditional DCs) were found in those acute inflammatory lesions ( Figure 3B). By contrast, control lung samples harvested after PBS inhalation contained almost no hybrid cells.…”

Dendritic Cell-Derived Tumor Necrosis Factor α Modifies Airway Epithelial Cell Responses

“…In addition, a recent study showed that DC-derived TNFα differed between mouse strains and that TNFα levels played a role in IL-17A production in the lung [35]. We have recently shown an increase in IL-17A following a single exposure to GC frass, as well as following adoptive transfer of GC frass-pulsed mDC [36]. While we did not address this in the current study, based on the work by Fei et al [35] it is possible that the DC-derived TNFα could be mediating the increase in IL-17A.…”

Allergic Inflammation: The Enemy Within

“…While the pulmonary system [4,5] is susceptible to allergic airway disease on activation by such diverse challenges as ambient air pollutants [4] and indoor allergens such as German cockroach frass [5] , the innate immune system fulfills an important role in the pathogenesis of allergic atopic dermatitis [6] . In complementary studies, Bezemer et al [4] and Page et al [5] show that ambient airborne pollutants and German cockroach frass, respectively, can promote a rapid onset of allergic inflammation via activation of stimulatory myeloid dendritic cells [4,5] . Conceptual frameworks that advanced our understanding of how the pulmonary innate immune system is modulated by ambient pollutants, xenobiotics and respirable areoallergens have also been previously discussed [6,7] .…”