The impairment in the NLRP3-induced NO secretion renders astrocytes highly permissive to T. cruzi replication

Abstract

Trypanossoma cruzi (T. cruzi), the causative protozoan of Chagas disease (CD) invades many cell types, including central nervous system (CNS) cells triggering local lesions and neurological impact. Previous work from our group described NLRP3 inflammasomes as central effectors for the parasite control by macrophages. Recent evidences demonstrate that NLRP3 can be activated in CNS cells with controversial consequences to the control of infections and inflammatory pathologies. However, the relative contribution of NLRP3 in different cell types remains to be elucidated. In this article, we described an effector response mediated by NLRP3 that works on microglia but not on astrocytes to control T. cruzi infection. Despite T. cruzi ability to invade astrocytes and microglia, astrocytes were clearly more permissive to parasite replication. Moreover, the absence of NLRP3 renders microglia but not astrocytes more permissive to T. cruzi replication. In fact, microglia but not astrocytes were able to secrete NLRP3-dependent IL-1 and NO in response to T. cruzi. Importantly, the pharmacological inhibition of iNOS with aminoguanidine resulted in a significant increase in the numbers of amastigotes found in microglia from wild-type but not from NLRP3 −/− mice, indicating the importance of NLRP3-mediated NO secretion to the infection control by these cells. Taken together, our findings revealed that T. cruzi differentially activates NLRP3 inflammasomes in astrocytes and microglia and established a role for these platforms in the control of a protozoan infection by glial cells from CNS. K E Y W O R D S NLRP3, T. cruzi, astrocytes, microglia, nitric oxide associated molecular patterns (DAMPs) (revised by Kigerl et al. 3 ). Inflammasomes are cytosolic complexes composed by multiple proteins that assemble in cell cytoplasm after DAMPs or PAMPs stimulation. 4-6 The stimulation is sensed by cytosolic receptors such as 202 PACHECO ET AL.the NOD-leucin rich repeats (LRR)-containing receptors (NLRs), which oligomerize and start the formation of cytoplasmatic complexes resulting in the recruitment and activation of caspase-1. Active caspase-1 cleaves pro-IL-1 , pro-IL-18, leading to the secretion of mature IL-1 and IL-18. Caspase-1 and caspase-11 also cleave gasdermin-D (GsmD), the effector protein of an inflammatory process of cell death named pyroptosis. 7,8 In addition to the maturation and secretion of IL-1 and IL-18 and induction of pyroptosis, inflammasomes also activate other microbicidal responses (reviewed in refs. 9,10). In this sense, our group demonstrated that the induction of NO through NLRC4 11,12 and NLRP3 13 inflammasomes is involved in the clearance of pathogens by macrophages.The role of inflammasomes in neuroinflamation has been described in many situations from sterile spinal cord injury (SCI), Alzheimer Disease (AD), multiple sclerosis (MS), and others 14 to bacterial and viral infections such as Legionella pneumophila, 15 Brucella abortus, 16 Staphylococcus aureus,17,18 Zika virus, 19 and many others. For each cont...

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Role of Inflammasomes in HIV-1 and Drug Abuse Mediated Neuroinflammaging

“…As described above, the ongoing neuroinflammation is reinforced by key innate immune sensor(s) for danger signals referred to as inflammasomes. In addition to microglia, astrocytes also express various members of the inflammasome family, as reported in various disease models [ 78 , 80 , 129 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 ]. NLRP1 is the first reported inflammasome expressed in the rat primary cortical astrocytes that is activated by purinergic receptors [ 174 ].…”