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Allergic asthma consists of diverse immune phenotypes exhibiting differential lung pathology, remodeling of the respiratory tract and mucociliary bronchial clearance. These diverse inflammatory immune mechanisms may promote or resist microbial infections in allergic human and mouse models. IL-6 governs optimal T-cell and inflammatory response leading to the resolution of bacterial and viral infections in respiratory airways. Additionally, IL-6 plays an important role in maintaining the integrity of airway barrier response during microbial infections. We hypothesized that lung IL-6 responses alleviate Streptococcus pneumoniae (Spn) pathogenesis during fungal allergic asthma caused by Aspergillus fumigatus. Using a murine Aspergillus fumigatus asthma model, we show that IL-6 deficiency exacerbates lung inflammation and promotes Spn disease pathogenesis in allergic host. IL-6 deficiency was associated with increased lung damage, which correlated with higher levels of lung eosinophilia, inflammatory cytokines and chemokines. Additionally, IL-6 deficiency correlated with increased TGF-β1 cytokine levels, increased epithelial-mesenchymal transition and dysregulated epithelial barrier proteins in asthmatic mice. We conclude that IL-6 offers a significant protective role in the control of Spn pathogenesis during allergic asthma by regulation of immune cell recruitment and maintenance of lung epithelial barrier integrity.

CD40 plays dual immunoregulatory roles in Leishmania major infection and tumor regression. The functional duality emerges from CD40-induced reciprocal p38MAPK and ERK-1/2 phosphorylations. Because phosphotyrosine-based signaling in hematopoietic cells is regulated by the phosphotyrosine phosphatase SHP-1, which is not implied in CD40 signaling, we examined whether SHP-1 played any roles in CD40-induced reciprocal signaling and anti-leishmanial function. We observed that a weaker CD40 stimulation increased SHP-1 activation. ERK-1/2 inhibition or p38MAPK overexpression inhibited CD40-induced SHP-1 activation. An ultra-low-dose, CD40-induced p38MAPK phosphorylation was enhanced by SHP-1 inhibition but reduced by SHP-1 overexpression. A reverse profile was observed with ERK-1/2 phosphorylation. SHP-1 inhibition reduced syk phosphorylation but increased lyn phosphorylation; syk inhibition reduced but lyn inhibition enhanced CD40-induced SHP-1 phosphorylation. Corroborating these findings, in L. major–infected macrophages, CD40-induced SHP-1 phosphorylation increased and SHP-1 inhibition enhanced CD40-induced p38MAPK activation and inducible NO synthase expression. IL-10 enhanced SHP-1 phosphorylation and CD40-induced ERK-1/2 phosphorylation but reduced the CD40-induced p38MAPK phosphorylation, whereas anti–IL-10 Ab exhibited reverse effects on these CD40-induced functions, identifying IL-10 as a crucial element in the SHP-1-MAPK feedback system. Lentivirally overexpressed SHP-1 rendered resistant C57BL/6 mice susceptible to the infection. Lentivirally expressed SHP-1 short hairpin RNA enhanced the CD40-induced L. major parasite killing in susceptible BALB/c mice. Thus, we establish an SHP-1–centered feedback system wherein SHP-1 modulates CD40-induced p38MAPK activation threshold and reciprocal ERK-1/2 activation, establishing itself as a critical regulator of CD40 signaling reciprocity and mechanistically re-emphasizing its role as a potential target against the diseases where CD40 is involved.