Figure 7.

Cytokine Response in HO-1 LysM Mice and Proposed Model for HO-1-Mediated Protection against Mtb Infection

(A–K) Cytokine analysis (A), IL-2 (B), IL-3 (C), IL-5 (D), IL-6 (E), IL-10 (F), IL-17A (G), MIP-1α (H), MIP-1β (I), G-CSF (J), KC (K) in the BALF of uninfected and Mtb-infected HO-1^LysM+/+ and HO-1^LysM−/− mice at 6, 12, and 18 weeks post-infection. n = 4 for each time point. Statistical testing was performed using the unpaired Student’s t test. Data are presented as mean ± SEM. ^∗p < 0.05, ^∗∗p < 0.01, ^∗∗∗p < 0.001.

(L) Proposed model for HO-1-mediated protection during Mtb infection. Mtb infection induces HO-1 expression and its downstream enzymatic cascade. Together with its enzymatic products and ferritin, which is induced by HO-1, HO-1 protects against TB immunopathology and thereby contributes to overall TB disease tolerance via its anti-oxidant, anti-inflammatory, and anti-proliferative properties. Therefore, maintaining the physiological levels of HO-1 is important to limit TB disease pathology (green shaded area). Contrarily, in HO-1-deficient conditions, the levels of key pro-inflammatory cytokines are significantly elevated. This results in rapid and dysregulated myeloid cell infiltration to the infected sites, which results in significantly elevated levels of ROS and RNS as well as rapid karyorrhexis and NETosis. ROS and RNS also generate increased localized concentrations of peroxynitrite (ONOO⁻) and subsequent suppression of T cell responses. In addition, Mtb infection also causes endothelial injury and intravascular coagulation, resulting in significant accumulation of heme, a potent proinflammatory and pro-oxidant molecule. Excess heme overwhelms the cytoprotective activity of HO-1, thereby contributing pro-oxidant-mediated inflammatory responses. Together, these dysregulated inflammatory responses result in chronic TB immunopathology and rapid disease progression (red shaded area).