Innate Immunity II: Understanding the Role of Inflammasome in the Innate Immune Response, Study notes of Biotechnology

Download Innate Immunity II: Understanding the Role of Inflammasome in the Innate Immune Response and more Study notes Biotechnology in PDF only on Docsity!

Innate Immunity II

Integration Lindsay Nicholson Advanced Immunology L2^ [email protected]

-^ Lecture 1^ –^

Defining Innate Immunity – Recognition and effector

mechanisms (I)

-^ Lecture 2^ –^

Recognition and effector

mechanisms (II)

-^ Integration of innate and adaptive immuneresponses

Innate Immunity 2 –

Key Concepts

-^ Extracellular and intracellular sensing •^ Pathways to NF-

κB and the inflammasome

-^ Monocyte

recruitment

-^ Macrophage differentiation •^ Innate immune activation regulates theprogress of an immune response •^ Adaptive immune response regulates thenature of the innate immune response

An introduction to the

inflammasome

-^ Inflammation involves the co-ordinatedupregulation

of a number of genes

-^ These are co-ordinated by specifictranscription factors, particularly NF-

κB

-^ Multiple different ‘danger’

signals are co-

ordinated to a common final pathway • This common final pathway has beencalled the inflammasome

Summary 1

-^ Multiple activators for the inflammasome^ through Nalp1 and Nalp3 •^ Common activation pathway leading toIL-

β^ secretion

-^ Genetic defects lead to inheritedinflammatory conditions •^ Treatment with anti-IL1R is effective

Integration of the Innate Immune

Response

-^ Extracellular and Cellular Mechanisms •^ Extracellular signals •^ PAMPs/MAMPs •^ Danger •^ Complement, proteolysis of extra-cellular matrix, actingas endogenous adjuvants •^ Cellular responses •^ Receptor dependent recruitment of neutrophils

and

macrophages in early inflammation • MyD88 adapter protein key signalling molecule • Leads to NF-

κB^ driven gene transcription

Effector

Mechanisms of the InnateImmune Response

Group

Examples

Cytokines

IL-1,^ IL-

, TNFα

, IL-12, IL-15, IL- 18, MIF, IL-

Chemokines

IL-8, MIP-1a, MIP-1b, MCP-1,MCP-

Lipid mediators

PAF, eicosanoids

(prostaglandins, leukotrienes, thromboxane,etc), tissue factor

Oxygen radicals

Superoxide and hydroxyl radical,nitric oxide

Killer cell products

Perforin, caspase

activators, FasL.

Summary 2

-^ Innate immune system receptors onleukocytes process information from theenvironment •^ They produce effector

molecules that

orchestrate the ongoing immune response

Macrophage life stories Nature Reviews Immunology 3, 23 -

35 2003

Macrophage life stories

Summary 3

-^ Macrophages express class II and canfunction as professional APCs •^ Recruited macrophages are dynamicrelatively short lived leukocytes

Macrophages and inflammation • Inflammation e.g. peritonitis

Increased promonocyte

production

Increased in the numbers of leucocytes in the blood Decrease in the mean half-life of the circulating cells

-^ During acute inflammation most macrophages andneutrophils

derive from the bone marrow via the circulation • Mechanisms^ Release of soluble activators effecting endotheliume.g. chemokines^ Upregulation

of integrins/addressins

on endothelial

cells Signals to retain cells in tissues Signals to the bone marrow

Potent activation by innate stimuli

10000 Macrophages in Culture^1000100 Nitrite (ng/ml)^101

Interferon gammaLPS

Sarah Morwood. Unpublished data.

-^ Macrophages arevery responsive tothe environment

0 2 4 6^ Time (hrs)

8 10 12

14

(^8000600040002000) NO (nM)^0

MediumLPS 0.1LPS 1.0IFN-g

Macrophages and inflammation Ben Raveney. Unpublished data.