Burn Injury Triggered Dysfunction in Dendritic Cell Response to TLR9 Activation and Resulted in Skewed T Cell Functions

Abstract

Severe trauma such as burn injury is often associated with a systemic inflammatory syndrome characterized by a hyperactive innate immune response and suppressed adaptive immune function. Dendritic cells (DCs), which sense pathogens via their Toll-like receptors (TLRs), play a pivotal role in protecting the host against infections. The effect of burn injury on TLR-mediated DC function is a debated topic and the mechanism controlling the purported immunosuppressive response remains to be elucidated. Here we examined the effects of burn injury on splenic conventional DC (cDC) and plasmacytoid DC (pDC) responses to TLR9 activation. We demonstrate that, following burn trauma, splenic cDCs’ cytokine production profile in response to TLR9 activation became anti-inflammatory dominant, with high production of IL-10 (>50% increase) and low production of IL-6, TNF-α and IL-12p70 (∼25–60% reduction). CD4+ T cells activated by these cDCs were defective in producing Th1 and Th17 cytokines. Furthermore, burn injury had a more accentuated effect on pDCs than on cDCs. Following TLR9 activation, pDCs displayed an immature phenotype with an impaired ability to secrete pro-inflammatory cytokines (IFN-α, IL-6 and TNF-α) and to activate T cell proliferation. Moreover, cDCs and pDCs from burn-injured mice had low transcript levels of TLR9 and several key molecules of the TLR signaling pathway. Although hyperactive innate immune response has been associated with severe injury, our data show to the contrary that DCs, as a key player in the innate immune system, had impaired TLR9 reactivity, an anti-inflammatory phenotype, and a dysfunctional T cell-priming ability. We conclude that burn injury induced impairments in DC immunobiology resulting in suppression of adaptive immune response. Targeted DC immunotherapies to promote their ability in triggering T cell immunity may represent a strategy to improve immune defenses against infection following burn injury.

Perturbed MafB/GATA1 axis after burn trauma bares the potential mechanism for immune suppression and anemia of critical illness

“…CDPs (Lin neg c-Kit med Flt3 + M-CSFR + ) and stem and progenitor cells (Lin neg c-Kit hi ) can generate both pDC and cDC in response to the cytokines Flt3L and GM-CSF. In a recent report, burn injury had a more accentuated effect on pDCs than on cDCs [40]. In fact, human BM progenitors with pDC potential [39] express M-CSFR.…”

Toll-Like Receptor Signaling in Burn Wound Healing and Scarring

“…46 Furthermore, from 1 to 7 days following burn, spleen cells were primed to produce greater amounts of pro-inflammatory cytokines after ex vivo exposure to TLR2 and TLR4 ligands; and burn-injured mice challenged with LPS expressed higher levels of inflammatory cytokines in the lung, liver, spleen, and plasma, primarily due to dendritic cells and macrophages, as judged by intracellular cytokine staining. 47 Moreover, increased TLR2 or TLR4 signaling in Kupffer cells has been suggested to be a source of elevated circulating cytokines in burned mice.…”

The Immune Response to Skin Trauma Is Dependent on the Etiology of Injury in a Mouse Model of Burn and Excision

“…Burn injury has been shown to decrease cDC (Patenaude et al, 2010;Shen et al, 2012) and pDC (Shen et al, 2012) number in both local draining lymph tissue and the spleen, with DCs possessing an anti-inflammatory phenotype and dysfunctional T cell-priming ability in the acute post-injury phase (Patenaude et al, 2010;Van den Berg et al, 2011).…”