Caspase-1 and Caspase-11 Mediate Pyroptosis, Inflammation, and Control of Brucella Joint Infection

Abstract

Brucellosis, caused by the intracellular bacterial pathogen is a zoonotic disease for which arthritis is the most common focal complication in humans. Here we investigated the role of inflammasomes and their effectors, including IL-1, IL-18 and pyroptosis, on inflammation and control of infection during-induced arthritis. Early in infection, both caspase-1 and caspase-11 were found to initiate joint inflammation and pro-inflammatory cytokine production. However, by one week post-infection caspase-1 and caspase-11 also contributed to control of joint infection. Inflammasome dependent restriction of joint burdens did not require AIM2 or NLRP3. IL-1R had a modest effect on -induced joint swelling, but mice lacking IL-1R were not impaired in their ability to control infection of the joint by In contrast, IL-18 contributed to the initiation of joint swelling and control of joint infection. Caspase1/11-dependent cell death was observed, and studies demonstrated caspase-1 and caspase-11 both induce pyroptosis which limited infection in macrophages. LPS alone was also able to induce caspase-11 dependent pyroptosis. Collectively these data demonstrate inflammasomes induce inflammation in an IL-18 dependent manner, and inflammasome-dependent IL-18 and pyroptosis restrict infection.

IFN-γ-dependent nitric oxide suppresses Brucella-induced arthritis by inhibition of inflammasome activation

“…Recently, we reported that inflammasomes induce joint inflammation, but also contribute to control of infection during Brucella ‐induced arthritis . Inflammasomes are multiprotein structures that use sensors, such as NLRP3 and AIM2, to detect intracellular, cytosolic threats .…”

Caspase-11 Non-Canonical Inflammasome: Emerging Activator and Regulator of Infection-Mediated Inflammatory Responses

“…induction and activation of caspase-11 in macrophages [25][26][27]. Although the mechanism of TRIF-induced activation of the caspase-11 non-canonical inflammasome is still unclear, TRIF in the TLR-TRIF axis is a critical molecule to activate caspase-11 non-canonical inflammasome during the inflammatory responses.…”

“…TIR-domain-containing adapter-inducing interferon β (TRIF) is an intracellular TLR adaptor to transduce the inflammatory signal cascades from TLRs in the inflammatory cells [7]. TRIF was reported as an activator of the caspase-11 non-canonical inflammasome i.e., infection of cells with Gram-negative bacteria induced the TRIF signaling pathway in macrophages, leading to the induction and activation of caspase-11 in macrophages [25][26][27]. Although the mechanism of TRIF-induced activation of the caspase-11 non-canonical inflammasome is still unclear, TRIF in the TLR-TRIF axis is a critical molecule to activate caspase-11 non-canonical inflammasome during the inflammatory responses.…”

Guanylate-binding proteins at the crossroad of noncanonical inflammasome activation during bacterial infections

“…In that case, caspase‐11 deficiency augmented bacterial burden in lungs, spleen, and liver . Similarly, caspase‐11 controlled Brucella melitensis joint infection and exacerbated joint inflammatory response against this pathogen . Moreover, recent data revealed that during B. abortus systemic infection, caspase‐11 −/− mice are more susceptible compared to wild‐type animals and they recruited fewer immune cells such as neutrophils, Mϕ s, and dendritic cells (DCs) in mouse spleens .…”

“…34 Similarly, caspase-11 controlled Brucella melitensis joint infection and exacerbated joint inflammatory response against this pathogen. 35 Moreover, recent data revealed that during B. abortus systemic infection, caspase-11 −/− mice are more susceptible compared to wild-type animals and they recruited fewer immune cells such as neutrophils, M s, and dendritic cells (DCs) in mouse spleens. 36 Additionally, Gram-negative bacteria such as Burkholderia pseudomallei and B. thailandensis that naturally invade the cytosol are targeted by caspase-11.…”