7. Innate immunity 4: Local inflammation; central to innate immunity and the initiation of adaptive immune responses

When and how does the body generate local inflammation?

• Triggered by infection or tissue damage

• Local production of inflammatory cytokines/chemokines

• Key activations:

  • IL-1β & TNF-α

  • Caspase-1 inflammasome

  • Complement system

  • Type I interferons

• Outcomes: Antimicrobial responses + recognition of self-components

Why is local inflammation important for vaccination?

• Induces innate immunity → adaptive immunity

• Acts as cornerstone for successful vaccination

• Cytokine “milieu” at site shapes memory cell response

• Strength & type of local inflammation influence memory duration (1 yr – 10 yrs or more)

  • Determines successful vs. unsuccessful vaccination

What are cytokines and what are their types?

• Small proteins (15–25 kDa) released in various cells, act like hormones

• Functions in intracrine, autocrine, justacrine, paracrine, endocrine, and exocrine manner.

• Types:

  • Interleukins (IL): from leukocytes

  • Myokines: from muscle cells (ex: IL-15)

  • Adipokines: from fat cells (produce massive amounts of cytokines)

  • Chemokines: chemo-attractant cytokines

What cytokines do macrophages secrete during local infection?

• Macrophages are ready to receive DAMP/PAMP signals → release cytokines if they can’t kill pathogen

• Local vs. systemic effects

  • Local: Exocrine and paracrine cytokine action for neighbouring cells

  • Systemic: Endocrine action in circulation → fever (one of the best innate  responses)

• Important cytokines: IL-1β, TNF-α, TL-6, CXCL8, IL-12

  • IFN-α/β/λ and IL-15 have direct anti-microbial activity

What are the four classical signs of local inflammation?

1. Redness (increased blood flow)

2. Heat (high temperature due to increased blood flow)

3. Swelling

4. Pain

How does local inflammation combat infection?

• Raises local/systemic temperature

• Delivers additional effectors & molecules to infection site

• Creates physical barrier to limit spread (blood vessel becomes dilated → plasma fluid gets out of blood → clots into bump)

  • Painful caused by pressure to nerves in the area

• Triggers adaptive immunity

For an effective immune response, how do immune cells reach the infection site?

• How do they know? Chemotactic signals (chemokines)

• How do they get there? Adhesion molecules (addressins) & migration pathways

What are “addressins” in immunity?

Adhesion molecules that guide leukocyte migration:

• Selectins

• Integrins

• Ig family

What role do selectins play in leukocyte interaction?

• Expressed in endothelial cells (cells that line blood vessels)
  Cytokines produced by macrophages activate endothelial cells locally to express those selectins

• Bind carbohydrates → initiate leukocyte-endothelial contact

• Examples (don’t need to know):

  • P-selectin: on activated endothelium & platelets

  • E-selectin: on activated endothelium

What are integrins and where are they expressed?

• Large family of adhesion molecules

• Expressed on leukocytes (immune cells)

• Work with selectins (which are on endothelial cells)

• Analogy:

  • Highway = blood vessel (endothelium)

  • Vehicles = leukocytes (integrins on them)

• Low baseline expression → upregulated with cytokines → high integrin levels

What are ICAMs/VCAMs and when are they expressed?

• Belong to Ig superfamily

• Expressed on endothelial cells

• Normally low/absent

• Upregulated during inflammation (triggered by cytokines/chemokines)

• Act as receptors for integrins on leukocytes

• 3 key adhesion families:

  • Selectins → endothelial cells

  • ICAMs/VCAMs → endothelial cells

  • Integrins → leukocytes

• Together mediate leukocyte adhesion + traffic during immune response

How do selectins help leukocytes migrate?

• All leukocytes have sugar-like receptor (s-Le^X ) that binds to selectin

• Binding is not strong enough to attach, but slows leukocyte down

  • Weak selectin and s-Le^X binding → leukocytes roll along endothelium → prepares for firm adhesion

What happens when ICAMs and integrins strongly bind during inflammation?

• Strong ICAM–integrin binding = firm adhesion (“full brake”)

• Concentration-dependent → highest at site of injury

• Leukocytes (cars) come to complete stop on endothelium (highway)

• Next step: transmigration (diapedesis)

  • Endothelial cells rearrange cytoskeleton → form pores

  • Allows leukocytes to exit blood vessel into tissue

What are the 4 steps of leukocyte migration into infected tissue?

• Rolling adhesion

• Tight binding

• Diapedesis (squeezing between endothelial cells)

• Migration along chemokine gradient

How do immune cells know where to go after leaving the bloodstream?

• Step 1: Address recognition → ICAM–integrin binding stops leukocytes

• Step 2: Chemotaxis → cells follow chemokine gradients

  • Highest chemokine concentration = site of injury/infection

  • Cells express chemokine receptors → move toward source

• Movement: cytoskeleton rearranges → cells become pointy & crawl through extracellular matrix

• Clinical relevance:

  • Basis for cancer immunotherapy → induce tumors to release chemokines to attract immune cells

• Must be tightly coordinated → imbalance = harmful (e.g., excessive inflammation, fever)

How do cytokines coordinate systemic immune responses?

• Liver → IL-6 stimulates production of innate molecules (CRP, complement)

• Bone marrow → cytokines signal stem cells to increase immune cell production (energetically costly)

• Hypothalamus → raises body temperature (fever)

  • Short-term: shivering → rapid ATP + heat

  • Long-term: sustained higher temperature aids defense

• Fat & muscle → contribute energy/heat

• Dendritic cells → antigen-presenting cells, key for activating adaptive immunity

• Overall: requires tight coordination across organs for effective protection

Why is the liver critical for innate immunity, and how does liver function affect immune response?

• Liver produces key innate molecules: CRP, mannose-binding protein, serum amyloid, antimicrobial factors

• Proper liver function = effective innate immunity

• Fatty liver/poor liver function → weaker response

  • Explains variation in vaccine or inflammation responses

• Age factor: younger people → stronger responses (better liver function); older people → weaker responses

Why is regulation of local vs systemic inflammation critical?

• Local inflammation → protective, controls pathogens, induces adaptive immunity

• Systemic inflammation → dangerous, can cause widespread endothelial activation, plasma leakage, organ failure → high mortality (~95%)

• Fine balance needed: uncontrolled systemic response = shock, kidney/liver/brain damage

• Immune deregulation = main cause of damage; proper coordination prevents this

• Innate & adaptive systems:

  • 99% protection comes from them

  • ~90% damage can also come from them if unregulated

Why is systemic inflammation/shock more dangerous in males?

Not fully understood, likely linked to sex hormone differences and immune regulation

Summary: What sequence of events occurs in tissue injury & infection?

1. Prevent infection → barriers, first-line defenses

2. Innate killing → phagocytes, antimicrobial molecules

3. Recognition → detect pathogen via PRRs, PAMPs

4. Induction of local inflammation → recruit immune cells, start tissue response

5. Adaptive immunity → antigen presentation → specific T/B cell response

• Takeaway: inflammation is central; essential for vaccine response and all disease processes