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Inflammation Luigi Racioppi, M. D. , Ph. D. Associate Professor General Pathology-Immunology

Information and sources Contact: ü Dipartimento di Medicina Molecolare e Biotecnologie Mediche racioppi@unina. it ü Division of Cell Therapy and Hematological malignancies Duke University, Durham, NC, USA luigi. racioppi@duke. edu ü ü ü Selected reviews and original articles Luigi Racioppi Unina Website Dropbox Skype account (raciopppi 2006) Webex

General features and causes of inflammation Learning Objectives: ü Understand biological and clinical significance of the inflammatory response. ü Understand functions of main components of the inflammatory response. ü Understand causes of the inflammatory response. ü Understand outcomes of the inflammatory response.

Cardinal signs of acute inflammation

Sequence of events in an inflammatory reaction. ü Response of vascularized tissues to damage. ü Cells and molecules of host defense from the circulation move to the damaged sites. ü Why: eliminate the offending agents and repair damaged tissue,

Causes of inflammation Cell 2010 140, 871 -882 DOI: (10. 1016/j. cell. 2010. 029)

Definitions and General Features of inflammation

Disorders caused by Inflammatory response

Disorders caused by inflammation Asthma Pulmonary fibrosis Septic schock Atherosclerosis

Recognition of injurious agent Learning Objectives: ü Understand how microbes and danger stimuli are recognized ü Understand the role of TLRs, inflammasome and nucleic acid sensors in the triggering of the inflammatory response ü Understand the role of apoptosis, necroptosis and pyroptosis in the inflammatory response

Mammalian TLR signaling pathways Nature Reviews Immunology 13, 453– 460 (2013) doi: 10. 1038/nri 3446

Inflammasome ü TLRs/PAMP induces. NLRP 3 and IL 1 b synthesis (S 1) ü ASC is ubiquitinated and phosphorylated (S 1) ü Relocalization of NLR 3 to mithocondria (S 2) ü Inflammasome oligomerization occurs Nature Medicine 21, 677– 687 (2015) doi: 10. 1038/nm. 3893

NLRC 4, AIM 2 and noncanonical NLRP 3 inflammasome activation Nature Medicine 21, 677– 687 (2015) doi: 10. 1038/nm. 3893

Mechanisms of NLRP 3 inflammasome action in Alzheimer's diseases Nature Medicine 21, 677– 687 (2015) doi: 10. 1038/nm. 3893

Mechanism of inflammasome activation in inflammatory disease ü Atherosclerosis: free fatty acids (FFA) prime NLRP 3 inflammasome through TLR 2 TLR 4 signaling. ü In type 2 diabetes (T 2 D), the NLRP 3 inflammasome is activated in both islet β-cells and myeloid cells. ü Saturated fatty acid (SFA) prime NLRP 3 inflammasome through an increase in mitochondrial ROS (mt. ROS). Nature Medicine 21, 677– 687 (2015) doi: 10. 1038/nm. 3893

Nucleic acid sensor molecules ü MDA 5 and RIG-I serve as ds. RNA receptors ü MDA 5 binds to long ds. RNA ü RIG-I binds short ds. RNA © 2008 Saito et al. Takeshi Saito, and Michael Gale, Jr. J Exp Med 2008; 205: 1523 -1527

Effector mechanisms in lytic and nonlytic cell death Published by AAAS David Wallach et al. Science 2016; 352: aaf 2154

Induction of pyroptosis David Wallach et al. Science 2016; 352: aaf 2154

Summary

Vascular reaction and recruitment of leukocyte to the site of inflammation Learning Objectives: ü Understand the mechanism of the vascular reaction in the acute inflammatory response. ü Understand the mechanism of leukocytes recruitment. ü Understand the role of neutrophil in acute inflammation. ü Understand the molecular basis of diseases caused by defects in the recruitment mechanism of neutrophil to the inflammatory site.

Formation of exudates and transudates.

Vascular changes in acute inflammation

Nature of leukocyte infiltrates in inflammatory reactions

Properties of Neutrophils and Macrophages

Sequence of events in an inflammatory reaction

Endothelial and Leukocyte Adhesion Molecules

LFA-1 conformations https: //www. frontiersin. org/articles/10. 3389/fimmu. 2012. 00157/full

Neutrophil inside-out activation of LFA 1 https: //www. frontiersin. org/articles/10. 3389/fimmu. 2012. 00157/full

Genetic diseases of neutrophil migration (LADs) ü Autosomal recessive genetic disease in which there is a defect/deficiency with the adhesion molecules involved in the leukocyte extravasation process. ü Impaired ability of leukocytes to migrate of through the endothelium, typically resulting in a reduced immune response. ü LAD-1, LAD-2 and LAD-3 https: //cellbiology. med. unsw. edu. au/cellbiology/index. php/2012_Group_8_Project#LAD-3

Molecular and clinical features of LADs

Major Defects in Leukocyte Extravasation https: //cellbiology. med. unsw. edu. au/cellbiology/index. php/2012_Group_8

Neutrophil regulate the inflammatory response: role of IL-17 in LAD-1 https: //www. nidcr. nih. gov/Science. Spotlight/Interviewsby. Topic/Periodontal. Disease/Early-Onset-Periodontitis-Children. htm

Summary

Leukocyte activation and removal of offending agents Learning objectives üUnderstand the mechanism of leukocytes activation. üUnderstand the mechanism of microbes destruction in leukocytes (Phagocytosis, NET). üUnderstand the molecular bases of diseases caused by an altered destruction of microbes (CGC, NETs-associate disorders).

Leukocyte activation

Phagocytosis and intracellular destruction of microbes

Reactive oxygen species Nature Reviews Immunology 4, 181– 189 (2004) doi: 10. 1038/nri 1312

Structure of NOX and DUOX enzymes Nature Reviews Immunology 4, 181– 189 (2004) doi: 10. 1038/nri 1312

ROS generation by assembly of Phox regulatory proteins in phagocytes PKC, AKT Nature Reviews Immunology 4, 181– 189 (2004) doi: 10. 1038/nri 1312

Assembly of the phagocyte NADPH oxidase NOX 2. Karen Bedard, and Karl-Heinz Krause Physiol

ROS generation by NOX enzymes: topology and downstream effects Karen Bedard, and Karl-Heinz Krause

Defect of ROS production: CGD A 41 -year-old woman presented with chronic diarrhea for 3 years associated with significant weight loss. An ileocolonoscopy showed multiple well-defined rectal ulcers. Biopsies revealed reactive hyperplasia of the superficial and cryptic epithelium with extensive ulceration translated by the presence of exudate, as well as epithelioid granulomas with nucleated giant cells (Figure 2). Biopsies from the colon showed mild chronic inflammatory changes with an epithelioid granuloma.

Inflammatory bowel disease (IBD) is a chronic condition resulting from complex interactions between intestinal microbiota and host immunity in genetically predisposed individuals resulting an inappropriate mucosal immune activation. IBD encompasses two entities, Crohn disease and ulcerative colitis. The distinction between ulcerative colitis and Crohn disease is based, in large part, on the distribution of affected sites and the morphologic expression of disease at those sites (Fig. 15. 26; Table 15. 5). Ulcerative colitis is limited to the colon and rectum and extends only into the mucosa and submucosa. By contrast, Crohn disease, also referred to as regional enteritis (because of frequent ileal involvement), may involve any area of the gastrointestinal tract and is frequently transmural.

Although precise causes are not yet defined, most investigators believe that IBD results rom the combined effects of alterations in host interactions with intestinal microbiota, ntestinal epithelial dysfunction, aberrant mucosal immune responses, and altered composition of the gut microbiome. This view s supported by epidemiologic, genetic, and clinical studies as well as data from laboratory models of IBD

http: //gut. bmj. com/content/gutjnl/60/12/1739/F 2. large. jpg

Chronic Granulomatos Disease https: //openi. nlm. nih. gov/detailedresult. php? img=PMC 4550764_gr 1&req=4

Neutrophil extracellular traps (NETs)

Neutrophil extracellular traps (NETs) form via two pathways http: //www. nature. com. proxy. lib. duke. edu/articles/nri. 2017. 105

The formation of neutrophil extracellular traps (NETs) http: //www. nature. com. proxy. lib. duke. edu/articles/nri. 2017. 105

Neutrophil extracellular traps (NETs) cause pathology http: //www. nature. com. proxy. lib. duke. edu/articles/nri. 2017. 105

Summary

Cytokines cytokines involved in inflammatory reactions

Chemokines

Chemokine receptor and ligand pairings Gemma E. White et al. Pharmacol Rev 2013; 65:

Functional regions of chemokine receptors

Metalloproteases (MPPs) regulates chemokines activity at the inflammatory sites Richard A. Dean et al.

Summary