Inflammasome Components NALP 1 and 3 Show Distinct but Separate Expression Profiles in Human Tissues Suggesting a Site-specific Role in the Inflammatory Response

Abstract

Several autoinflammatory disorders such as Muckle-Wells syndrome are characterized by mutations in the NALP3/cryopyrin gene. NALP3 and NALP1 proteins can assemble to inflammasomes that activate caspase-1, resulting in the processing of pro-inflammatory cytokines IL-1beta and IL-18. The present study was designed to determine which cells and tissues express NALP1 and NALP3. Monoclonal antibodies were developed and their use revealed distinct distribution profiles of NALP1 and NALP3. Granulocytes, monocytes (very weakly), dendritic cells, and B and T cells all express NALP1 and NALP3. Highest levels of NALP1 are found in T cells and Langerhans cells. Furthermore, NALP1 is present in glandular epithelial structures such as stomach, gut, lung, and, surprisingly, in neurons and testis. In contrast to NALP1, NALP3 shows a more restricted tissue distribution with expression mainly in non-keratinizing epithelia in the oropharynx, esophagus, and ectocervix. Moreover, NALP3 expression is found in the urothelial layer in the bladder. Likewise, a difference in subcellular distribution between NALP1 and NALP3 is observed because NALP1 is localized mainly in the nucleus, whereas NALP3 is predominantly cytoplasmic. We propose that the presence of NALP3 in epithelial cells lining the oral and genital tracts allows the rapid sensing of invading pathogens, thereby triggering an innate immune response.

Activation and Regulation of Cellular Inflammasomes: Gaps in Our Knowledge for Central Nervous System Injury

“…21,22 In macrophages, NLRP1 expression is governed by several regulatory mechanisms and putative protein interactions. 23 The sterol regulatory element binding protein-1a basic helix-loop-helix zipper transcription factor differentially regulates the expression of Nlrp1a in hematopoietic cells. 24 At the posttranslational level, NLRP1 undergoes autocleavage at Ser 123 in the FIIND domain that is required for function.…”

Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders

“…In addition, several inflammasomes have been characterized in microglia including NLRP1, NLRP3, and NLRC4 (Walsh et al, 2014). Notably, several studies have characterized inflammasomes in neurons Kummer et al, 2007), which are capable of producing IL-1β (de Rivero Vaccari et al, 2009). The NLRP3 inflammasome has been the most studied inflammasome in the CNS (Walsh et al, 2014), and as expanded upon below, has also been the focus of the preponderance of studies into the role of inflammasomes in animal models of depression.…”

NADPH oxidase derived reactive oxygen species are involved in human neutrophil IL‐1β secretion but not in inflammasome activation

“…In contrast, the mechanisms involved in human neutrophil IL-1β processing and secretion remain to be elucidated. Previous studies have documented that human neutrophils express both NLRP3 and caspase-1 [15][16][17][18]. However, as neutrophil proteases were also implicated both in extracellular and intracellular pro-IL-1β processing [5,[19][20][21][22], the idea that prevails is that these cells process pro-IL-1β through a protease-dependent and caspase-1-independent mechanism [4].…”

“…Likewise, there is also evidence indicating that intracellular PR3 and elastase generate active IL-1β [22]. However, previous studies showed that human and mouse neutrophils express NLRP3 and that activity of caspase-1 is induced upon LPS stimulation [15][16][17][18]31]. Moreover, these studies showed the ability of human neutrophils to release IL-1β in a caspase-1-dependent fashion in response to high concentrations of LPS (1 μg/mL) [17].…”