Mucosal Homeostasis In The Healthy Lung

Question 1

Pneumonia video

Answer 1

explained (not really focus of lecture)

Question 2

Homeostasis in the alveolar space

Answer 2

Differentiation of challenges without bystander damage in a tissue that is fragile!

lungs in constant contact w/ harmless or pathogenic elements
e.g. grass, dust mites, spores cats, food

Tissue Histology:
Type 1 and 2 AEC

equilibrium b/w normal gas exchange and inflammation

Question 3

Immune cell interactions in the healthy lung

Answer 3

The lung has specialised
tissue-resident immune cells
* Dendritic cells
* Alveolar macrophages
* Regulatory T cells

Question 4

Meet the alveolar macrophage (7+1 marks)

Answer 4

• CD11c ++ SiglecF+ F4/80 int
• Resident phagocytic patrolling cells
• Pro and anti inflammatory
• Remove apoptotic cells by efferocytosis
• Induce regulatory T cells via retinoic acid
• Mixed functional phenotype – highly phagocytic
  and capable of producing TNF-⍺ and IL-1 but also
  responsive to IL-4 and able to drive type 2 inflammation
  as well as potentially wound healing – a response that is site specific
• Important sentinels in asthma – depletion exacerbates disease

Question 5

Alveolar macrophage ontogeny and turnover

Answer 5

diagram

Question 6

Macrophage activation is a balancing act

Answer 6

no need to memorise receptors fully!!!!
* Activation of alveolar macrophages
depends on a balance between signals
leading to activation and inhibition
* In the absence of inflammation
regulation predominates through
negative signals
* The epithelia raises the threshold above
which macrophages get activated
* Negative signals are provided by the
airway epithelium and soluble
molecules like mucus
* Regulation is linked to macrophage
function i.e. clearance of apoptotic cells

Question 7

Homeostasis in the alveolar space
in situ negative regulation

Answer 7

• Regulation is highly
  dependent on contact
  with epithelia, setting a
  threshold above witch
  macrophages activate
• Antigen plus a disruption
  of the epithelia drives
  macrophage activity
• After inflammation the
  tissue adapts to a novel
  state of regulation – we
  are never the same after
  inflammation

Question 8

Control of innate immunity in the airway

Answer 8

images

Question 9

Regulation of alveolar macrophages in the absence of antigenic stimulation

Answer 9

images

Question 10

Alveolar macrophage shape the composition of the lung mucosal microbiome

Answer 10

CD200 – CD200R signals regulate macrophage activity and change the bacterial species present in the airway

image

Question 11

Infections alter the state of regulation in homeostasis by affecting macrophage function

Answer 11

The expression of CD200R by
macrophages increases as
Influenza infection proceeds
=
Leading to susceptibility to bacterial
pneumonia

Question 12

Inflammatory responses in asthma

Answer 12

video

Question 13

How do we study immune mechanisms behind susceptibility to
bacterial pneumonia during asthma?

Answer 13

HDM allergen exposure in mice
recapitulates a pathology that is
comparable to human Asthma

S.pneumoniae induces lethal pneumonia in asthmatic mice due to neutropenia

look at: Bacterial recovery
from tissues and Blunted neutrophil
recruitment

Question 14

What is different in alveolar macrophages in different states of altered health?

Answer 14

Apoptotic cells are present in most inflammatory conditions and their clearance is required

Question 15

Apoptotic cell clearance regulates alveolar macrophages

Answer 15

TAM receptors control cytokine production and TLR signalling
altering macrophage function

Apoptotic cell clearance is
a hallmark of resolution in
inflammation

Question 16

The role of sugars and the mucus

Answer 16

Siglec-F Sialic acid binding
immunoglobulin-type lectin

Siglec-F is expressed by alveolar
macrophages extracted by lavage

Macrophages interact with mucins both in “health” and in inflammation via Siglecs

Siglec-F signals decrease the expression of Trem2 and Axl on alveolar macrophages

Question 17

Key points

Answer 17

• Chronic conditions like asthma are not only or necessarily exacerbated by infection
• Individuals with chronic respiratory conditions (or after acute inflammation) have an altered state of health that affects their response to infections
• This altered state of health might be associated with a different level of regulation or activity of immune cells (alveolar macrophages) in the lungs
• Alveolar macrophages interact with the environment in different ways in homeostasis or after inflammation
• All of these principles seem to apply to multiple inflammatory conditions
• The integrity and activity of the epithelia is key to maintain homeostasis

Question 18

Altered macrophage regulation after inflammation

Answer 18

Alveolar macrophages are long-lived but do not return to the same state of regulation after inflammation

Question 19

Immune properties of epithelial cells (many cells)

Answer 19

images

Question 20

The diverse epithelial component and their interactions with resident and recruited immune cells

Answer 20

image

Question 21

Summary

Answer 21

• The lung mucosal epithelia is not just a barrier, it interacts with
  commensals and immune cells to maintain homeostasis and initiate
  regulated immune responses
• The lung epithelia express a group of receptors that provide signals that
  control and harness macrophage function
• Soluble factors also regulate macrophage function (environment)
• The integrity of the epithelia is essential to maintain mucosal immune homeostasis
• High expression of negative regulators, and negative feedback loops by TAM receptors, are predominant in resolution tipping the balance of macrophage function towards regulation
• Alveolar macrophages change their responsiveness with every
  inflammatory response and phenotypic changes might be prolonged suggesting a process of adaptation
• These data highlight the importance of understanding the mechanisms of mucosal regulation in health and the differed states of “altered health”

Question 22

Some key interactions between resident/recruited cells of the lung

Answer 22

diagram