Danger-associated molecular patterns and inflammatory bowel disease: is there a connection?

Area of Science:

• Immunology
• Gastroenterology
• Cell Biology

Background:

• The innate immune system maintains intestinal homeostasis by recognizing microbial and danger signals via pattern recognition receptors.
• Pathogen-associated molecular patterns (PAMPs) are well-established in Crohn's disease pathogenesis, unlike danger-associated molecular patterns (DAMPs).
• DAMPs, or alarmins, are intracellular molecules released from damaged cells, implicated in inflammatory conditions like inflammatory bowel disease (IBD).

Purpose of the Study:

• To investigate the role of DAMPs in the pathogenesis of inflammatory bowel disease (IBD).
• To explore the involvement of DAMPs in triggering the triggering receptor expressed on myeloid cells (TREM)-1-mediated inflammation.
• To assess the dual role of DAMPs and PAMPs in intestinal inflammation and barrier function.

Main Methods:

• Review of existing literature on innate immunity, PAMPs, DAMPs, and IBD.
• Analysis of evidence linking DAMPs to TREM-1 activation and pro-inflammatory effects in IBD.
• Examination of mouse models with deficiencies in inflammasome sensors (NLRP6, NLRC4) to assess colitis susceptibility.

Main Results:

• DAMPs contribute to and exacerbate colonic inflammation, particularly when activating innate immune cells in the intestinal lamina propria.
• Circumstantial evidence suggests DAMPs induce TREM-1-mediated inflammation observed in active IBD.
• Blocking TREM-1 interactions with an antagonistic peptide attenuated colonic inflammation progression in mouse models.
• Mice deficient in NLRP6 or NLRC4 inflammasome sensors showed enhanced susceptibility to colitis, indicating a role for DAMPs/PAMPs in barrier function.

Conclusions:

• DAMPs play a significant role in exacerbating IBD pathogenesis by activating innate immune cells.
• DAMPs are implicated as inducers of TREM-1-mediated inflammation in IBD.
• Both DAMPs and PAMPs are essential for maintaining intestinal epithelial barrier integrity, with deficiencies leading to increased colitis susceptibility.